- Enzalutamide is a hormone therapy that is used to treat advanced prostate cancer. It is given after chemotherapy and surgery to help the body destroy the cancer cells. A new possible way of treating prostate cancer is using a vaccine that may help stimulate the immune system. It will help white blood cells recognize and kill the cancer cells in and around the prostate. Researchers want to see whether this vaccine, given with enzalutamide, is more effective at treating advanced prostate cancer than enzalutamide alone.

Objectives:

- To compare the safety and effectiveness of enzalutamide with and without vaccine therapy for advanced prostate cancer.

Eligibility:

- Men at least 18 years of age who have advanced castration-resistant prostate cancer.

Design:

Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will be used to monitor the cancer before treatment.

Participants will be separated into two groups. One group will have enzalutamide and the study vaccine. The other group will have enzalutamide alone.

All participants will take enzalutamide once a day. They will take the drug during 4-week cycles of treatment.

Treatment will be monitored with frequent blood tests and imaging studies. Participants will continue to take the study drug for as long as the cancer does not grow and the side effects are not severe.

The vaccine group of participants will also have the new study vaccine. They will have a single injection on the first day of the first study cycle. There will be regular booster injections afterward. There will be one on day 15 of the first cycle, the first day of the second cycle. The vaccine will then be given every 4 weeks for the next four cycles, and then every 12 weeks (every 3 cycles) thereafter. Participants will continue to have the study vaccine for as long as the cancer does not grow and the side effects are not severe.

A recombinant fowlpox virus vector vaccine containing the genes for human PSA and three co-stimulatory molecules.

Biological: PROSTVAC-V/TRICOM

A recombinant vaccinia virus vector vaccine containing the genes for human PSA and three co-stimulatory molecules.

Drug: Enzalutamide (Xtandi)

An androgen receptor inhibitor.

Detailed Description:

Background:

Enzalutamide is a well-tolerated, modern androgen receptor antagonist (ARA) with more enhanced anti-tumor activity compared to previous ARAs. Phase III trial has demonstrated a 4.8 month improvement in survival and a 37% risk reduction in death in metastatic castration resistant prostate cancer (mCRPC) patients who have had previous docetaxel.

PROSTVAC is a therapeutic cancer vaccine which is designed to induce an anti-tumor immune response. In a randomized controlled Phase 2 trial, PROSTVAC therapy was associated with a prolongation of survival by 8.5 months in men with metastatic castrateresistant prostate cancer. An international Phase 3 trial is on-going.

Preclinical data has demonstrated that hormonal therapies such as ARAs can enhance the immune response through multiple mechanisms. Specifically, our group has shown that enzalutamide can increase thymic production of na(SqrRoot) ve T-cells, which could be activated by a cancer vaccine. Together, these data provide an important rationale to combine enzalutamide with PSA-TRICOM in mCRPC.

Data from the clinical trials with these therapies suggest that they are very well tolerated and without overlapping toxicity.

The study will randomize chemotherapy-naive, mCRPC patients to either enzalutamide alone or enzalutamide with PSA-TRICOM. Enzalutamide will be given at the standard dose of 160 mg daily.

PSA-TRICOM will be administered identical to the Phase III dosing with vaccine given week 1 (vaccinia-PSA-TRICOM, 2x10(8) units subcutaneously) and then week 3, 5 and then monthly fowlpox-vaccine (1x10(9) units subcutaneously).

After completing 6 months of vaccine, fowlpox-vaccine (1x10(9) units subcutaneously will be administered every 3 months. Patients will be treated until radiographic progression on scans using Prostate Cancer Working Group Criteria.

Chemotherapy-na(SqrRoot) ve with minimal or no symptoms related to prostate cancer.

Patients with history of autoimmune disease, brain/leptomeningeal metastasis, a second malignancy within 3 years of enrollment, or a severe co-morbid condition will be excluded.

Patients who have received abiraterone will be excluded

Patients will be stratified based on previous immunotherapy used as cancer treatment.

Eligibility

Ages Eligible for Study:

18 Years to 100 Years (Adult, Senior)

Genders Eligible for Study:

Male

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed prostate cancer confirmed by either the Laboratory of Pathology at the NIH Clinical Center or Walter Reed National Military Medical Center at Bethesda prior to starting this study. If no pathologic specimen is available, patients may enroll with a pathologist s report showing a histological diagnosis of prostate cancer and a clinical course consistent with the disease.

Castrate testosterone level (<50ng/dl or 1.7nmol /L)

Metastatic disease documented by one of the following:

Metastatic bone disease on an imaging study, or

Soft tissue disease documented by CT/MRI, or

Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone:

i. Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR

ii. PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria) If patients had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal.

The requirement for a 4-6 week withdrawal period following discontinuation of flutamide, nilutamide or bicalutamide only applies to patients who have been on these drugs for at least the prior 6 months. For all other patients they must stop bicalutamide, nilutamide or flutamide the day prior to enrollment.

Asymptomatic or mildly symptomatic from prostate cancer; no use of regularly scheduled opiate analgesics for prostate cancer-related pain

Patients must agree to continue to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy

Age greater than or equal to 18 years.

ECOG performance status less than or equal to 1 (Karnofsky greater than or equal to 80%).

Patients must have normal organ and marrow function as defined below:

absolute neutrophil count greater than or equal to 1,500/mcL

platelets greater than or equal to 100,000/mcL

total bilirubin within normal institutional limits; for patients with Gilbert s syndrome, total bilirubin less than or equal to 3.0mg/dL

AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal

The effects of enzalutamide alone or in combination with PSA-TRICOM on the developing human fetus are unknown. For this reason, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.

Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients who are immunocompromised as listed as follows:

Human immunodeficiency virus positivity due to the potential for decreased tolerance and may be at risk for severe side effects

Chronic administration (defined as daily or every other day for continued use >14 days) of systemic corticosteroids (including steroid eye drops) or other immune suppressive drugs, within 28 days before the first planned dose of PSA-TRICOM. Nasal, or inhaled steroid, and topical steroid creams for small body areas are not excluded.

Patients with history of seizure as an adult including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with anti-epileptic medications for the treatment of seizures or history of loss of consciousness. Also transient ischemic attack within 12 months prior to randomization will not be permitted.

Patients with second malignancy within 3 years of enrollment; Patients curatively treated non-melanoma skin cancers or carcinoma in situ of the bladder, are not excluded.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine)

History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis

Previous adverse reactions to smallpox vaccination

Unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczemoid skin disorders, or (d) immunocompromised individuals, such as those with HIV.

Any condition which, in the opinion of the investigator, would prevent full participation in this trial (including the long-term follow-up), or would interfere with the evaluation of the trial endpoints.

Patients with prior chemotherapy for nonmetastatic prostate cancer within a year are excluded.

Receipt of an investigational agent within 28 days (or 56 days for an antibody-based therapy) before the first planned dose of study drugs. (Immune checkpoint inhibitors that are antibody-based will only require 28 days before enrollment)

Use of herbal products that may decrease PSA levels (e.g. saw palmetto)

Any gastrointestinal disease that could hinder the absorption of enzalutamide.

Patients who have had chemotherapy for metastatic castration-resistant prostate cancer. (Patients who have had docetaxel for metastatic castration sensitive disease per CHAARTED Data35 may enroll as long as they did not have progressive disease while on docetaxel and are 6 months removed from treatment, with all treatment related toxicities resolving to at least grade 1.)

Patients who have received radiation therapy, radionuclide therapy or undergone surgery within certain duration (4 weeks) of enrollment

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01867333